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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0397
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 3 715-722
Copyright © 2008 by The Endocrine Society

Reduced High-Molecular-Weight Adiponectin and Elevated High-Sensitivity C-Reactive Protein Are Synergistic Risk Factors for Metabolic Syndrome in a Large-Scale Middle-Aged to Elderly Population: the Shimanami Health Promoting Program Study

Yasuharu Tabara1, Haruhiko Osawa1, Ryuichi Kawamoto, Rieko Tachibana-Iimori, Miyuki Yamamoto, Jun Nakura, Tetsuro Miki, Hideich Makino and Katsuhiko Kohara

Departments of Basic Medical Research and Education (Y.T.), Molecular and Genetic Medicine (H.O., H.M.), and Geriatric Medicine (R.T.-I., M.Y., J.N., T.M., K.K.), Ehime University Graduate School of Medicine, Ehime 791-0295, Japan; and Department of Internal Medicine (R.K.), Seiyo-city Nomura Hospital, Ehime 797-1212, Japan

Address all correspondence and requests for reprints to: Yasuharu Tabara, Ph.D., Department of Basic Medical Research and Education, Ehime University Graduate School of Medicines, Toon, Ehime 791-0295, Japan. E-mail: tabara{at}m.ehime-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: In Western countries, one of the most important modifiable targets for the prevention of cardiovascular diseases is metabolic syndrome. Adiponectin is an adipose tissue-specific plasma protein that inversely associates with metabolic syndrome. Among several molecular isoforms, high-molecular-weight (HMW) complex is considered the active form. Increased serum high-sensitivity C-reactive protein (hsCRP) concentration also associates with metabolic syndrome, and adiponectin could modulate plasma C-reactive protein levels. Here, through cross-sectional investigation, we investigated whether reduced HMW adiponectin and increased hsCRP levels in plasma are synergistically associated with metabolic syndrome. Measurement of HMW complex of adiponectin is one of the novelties of this study.

Design: We analyzed 1845 community-dwelling middle-aged to elderly subjects (62 ± 13 yr). Plasma HMW adiponectin levels were measured by ELISA. Clinical parameters were obtained from the subjects’ personal health records, evaluated at their annual medical check-up.

Results: Each component of metabolic syndrome, except for raised blood pressure, showed significantly lower plasma HMW adiponectin concentrations for both men and women (P < 0.001). In contrast, plasma hsCRP levels were significantly higher in subjects with metabolic disorders (P < 0.001). After adjusting for other confounding factors, HMW adiponectin [log normalized, odds ratio 0.084 (95% confidence interval 0.050–0.142), P < 0.001] and hsCRP [3.009 (2.175–4.163), P < 0.001] were identified as independent determinants of metabolic syndrome. In addition to the direct associations, we also observed a synergistic effect between these two molecules (F = 11.8, P < 0.001).

Conclusions: Reduced HMW adiponectin and elevated hsCRP are synergistically associated with the accumulation of metabolic disorders. The combination of these markers would be useful for identifying at-risk populations.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
In Western countries, one of the most important modifiable targets for the prevention of cardiovascular disease (CVD) is metabolic syndrome (MetS). MetS is a concept for clustering cardiovascular risk factors, including abdominal obesity, raised blood pressure (BP), hypertriglyceridemia, and impaired glucose tolerance (1). Several epidemiological studies have reported significant associations between MetS and coronary artery disease and stroke, as well as mortality (2, 3, 4). An accumulation of abdominal fat is thought to be the main contributing factor to the development of MetS.

Adipose tissue releases several products that apparently exacerbate or prevent metabolic disorders. Adiponectin is one of the adipose tissue-specific plasma proteins that can suppress atherosclerotic vascular changes (5, 6). The underlying mechanisms for the favorable effects of adiponectin are thought to be inhibition of the expression of adhesion molecules in vascular endothelial cells (7) and the formation of foam cells (8).

In epidemiological studies, obese subjects and subjects with MetS showed lower adiponectin levels (9, 10). Recently it was reported that body fat distribution is more important than body mass index (BMI) per se for adipocytokines profiles in elderly women (11). Plasma adiponectin levels were lower in central obese subjects, compared with peripheral or general obese subjects (11).

There are at least three forms of circulating adiponectin; a lower-molecular-weight trimer, a middle-molecular-weigh hexamer, and larger multimeric structures of high molecular weight (HMW) with 12 to 18 subunits (12). It was recently reported that the ratio of HMW adiponectin to total adiponectin or the HMW form itself was better correlated with glucose tolerance (13), thiazolidinedione treatment (14), and dietary intervention in obese subjects (15). It was also reported that the HMW adiponectin has vascular-protective activities by suppressing apoptosis of endothelial cells (16). Although the biological activity of adiponectin isoforms is controversial, these observations suggest that HMW complex is an active form of this protein. Recently, a HMW-specific ELISA was developed by Nakano et al. (17). They also reported that the determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating coronary artery disease in type 2 diabetic patients (18).

High-sensitivity (hs) C-reactive protein (CRP) is another marker for inflammation reflecting the early stage of atherosclerosis (19, 20). Several large-scale prospective studies have shown that plasma levels of hsCRP are strong independent predictors of the future risk of atherosclerotic events (21). Ouchi et al. (22) reported expression of CRP mRNA in adipose tissue and its negative correlation with adiponectin expression levels, suggesting a possible interaction between these two key molecules.

From these lines of evidence, we hypothesized that reduced adiponectin and increased hsCRP levels in plasma could be interactively associated with MetS. This paper reports on a cross-sectional epidemiological study conducted to clarify the hypothesis in a community-dwelling large-scale population. Measurement of HMW complex of adiponectin is one of novelties of this study. Our study also provides a clinical implication of HMW adiponectin in relation to MetS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

The present study is derived from the Shimanami Health Promoting Program, as a longitudinal epidemiological study evaluating factors relating to CVD, dementia, and death (23). Subjects were selected through a community-based annual medical check-up process. The sample population comprised 1873 middle-aged to elderly residents. For all these individuals, overnight fasting plasma samples were available for measuring HMW adiponectin, hsCRP. To incorporate a homeostasis model assessment of insulin resistance (HOMA-IR) into the analysis, we reduced the number of subjects from 1873 to 1845. The omitted subjects’ samples had a limited volume of plasma. We investigated the baseline characteristics of the study subjects (e.g. smoking and alcohol habits, medications, and history of CVD) in individual interviews using a structured questionnaire. Their daily alcohol consumption was measured using the Japanese liquor unit (in which 1 U corresponds to 22.9 g of ethanol). All study procedures were approved by the Ethics Committee of Ehime University Graduate School of Medicine, and each subject gave informed consent to participate.

Definition of MetS

Baseline clinical parameters were obtained from the subjects’ personal health records that were updated at their annual medical check-up. MetS was defined using the modified criteria of the National Cholesterol Education Program’s Adult Treatment Panel III report (24) as follows: 1) obesity: BMI 25 kg/m2 or greater according to the guidelines of the Japanese Society for the Study of Obesity (waist circumference was not available in this study) (25); 2) hypertriglyceridemia with a serum triglyceride concentration of 150 mg/dl or greater (1.69 mmol/liter); 3) low high-density lipoprotein (HDL) cholesterolemia with a serum HDL cholesterol concentration of less than 40 mg/dl (1.04 mmol/liter) in men and less than 50 mg/dl (1.30 mmol/liter) in women; 4) raised BP with systolic BP of 130 mm Hg or greater and/or diastolic BP of 85 mm Hg or greater and/or receiving antihypertensive medication; and 5) impaired glucose tolerance with serum glucose concentration of 110 mg/dl or greater (6.1 mmol/liter) and/or receiving antidiabetic medication (oral agents). BP was measured using an automatic cuff-oscillometric device with an appropriate-sized cuff on the left arm (BP-103i, Colin Co., Ltd., Aichi, Japan). The BP measurements were carried out after a resting period of at least 5 min in the sitting position. Subjects meeting three or more of these criteria were regarded as having MetS.

Measurement of plasma HMW adiponectin and hsCRP

Plasma samples were obtained from each subject after an overnight fast of more than 11 h. The samples were immediately frozen and stored at –80 C until measurements were taken. The plasma concentration of HMW adiponectin was determined using a recently developed ELISA system (Fujirebio Inc., Tokyo, Japan) (17). In brief, this assay system is composed of monoclonal antibodies against HMW adiponectin as solid phase and horseradish peroxidase as the detection antibody. The specificity of this monoclonal antibody has been described elsewhere. For the measurements, 100 µl of diluted (1:441) serum samples were used for the measurements. After 30 min of incubation with tetramethylbenzipine, absorbance was measured at 450 nm. Standardized HMW adiponectin concentrations were determined by human HMW adiponectin purified by gelatin-cellulofine column chromatography. The inter- and intraassay coefficient variations of the adiponectin assay were 4.4 and 9.7%, respectively.

Plasma hsCRP concentration was measured using a Behring BN II nephelometer (Dade Behring Inc., Marburg, Germany) (26, 27). The analytical performance of this ultrasensitive latex-enhanced immunoassay, which uses monoclonal anti-CRP antibodies, has been validated previously (26). The inter- and intraassay coefficient variations of the hsCRP assay were 3.2 and 6.7%, respectively.

Assessment of insulin resistance

We used HOMA-IR (28) as an index of insulin resistance. Subjects showing more than 1.73 of HOMA-IR were regarded as having insulin resistance according to previous studies involving Japanese subjects (29, 30). In brief, HOMA-IR of 1.73 was obtained as a corresponding value to the M value of 167.3 mg/m2·min (the mean value minus 1 SD), the rate of glucose infusion during the glucose clamp test. The sensitivity and specificity of this cutoff point for insulin resistance were 64.7 and 78.9%, respectively. The usefulness of this criterion in epidemiological studies has also been described elsewhere (30). The pathophysiological significance for the development of impaired glucose tolerance and type 2 diabetes mellitus between Japanese and Caucasians is another reason for the application of a lower HOMA-IR value as a cutoff point; secretion of insulin during the oral glucose tolerance test is significantly lower in Japanese (31). HOMA-IR was calculated as follows: HOMA-IR = [fasting immunoreactive insulin (microunits per milliliter) x fasting glucose (milligrams per deciliter)]/405.

Statistical analysis

The values are means ± SD unless otherwise specified. An ANOVA was used to test for statistical significance among groups. A post hoc analysis was performed with Dunnett’s test (Fig. 1Go). Factors independently associated with HMW adiponectin (see Table 2Go) and MetS (see Table 4Go) were assessed by a multiple regression analysis and a logistic regression analysis, respectively. The synergistic effect of HMW adiponectin and hsCRP was evaluated using a general linear model (Fig. 2Go). All analyses were performed with a commercially available statistical package (SPSS, version 14.0; SPSS Inc., Chicago, IL). Null hypotheses were rejected at P < 0.05 level of significance.


Figure 1
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  		FIG. 1. Accumulation of metabolic disorders and plasma adiponectin levels. Values are means ± SD. Metabolic disorders indicate obese, raised BP, impaired glucose tolerance, hypertriglyceridemia, and low HDL cholesterolemia. Number of subjects in each category is represented in the column. Asterisks indicate statistical significance, compared with the no metabolic disorders group. Statistical significance was assessed by ANOVA (overall P < 0.001), and Dunnett’s one-tailed test was used for the post hoc analysis.

 

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  		TABLE 2. Single and multiple regression analysis for plasma HMW adiponectin levels

 

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  		TABLE 4. Logistic regression analysis for MetS and insulin resistance

 

Figure 2
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  		FIG. 2. Synergistic effect of reduced HMW adiponectin and increased hsCRP. A, Mean accumulated number of the following metabolic disorders: obesity, raised BP, impaired glucose tolerance, hypertriglyceridemia, and low HDL cholesterolemia. B, HOMA-IR. Study subjects were divided into three groups (tertiles) according to plasma adiponectin and hsCRP levels. Each tertile was calculated within sex and then combined to avoid the gender differences. Number of subjects in each column was represented in A. Statistical significance was assessed by a general linear model adjusted for the following parameters: age, sex, current smoking, alcohol intake, and history of CVD. Medications (hypertension, diabetes mellitus, hyperlipidemia) were further adjusted in the analysis for HOMA-IR. Log normalized HMW adiponectin, hsCRP, and HOMA-IR were enrolled in the analyses.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of the study subjects are summarized in Table 1Go. The mean value of plasma HMW adiponectin levels was twice as high for the female subjects. This sex difference (β = –0.417, P < 0.001) was independent of BMI (β = –0.239, P < 0.001). We performed the gender-stratified analysis due to the larger differences in plasma HMW adiponectin level.


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  		TABLE 1. Baseline characteristics of the subjects (n = 1845)

 
The mean fasting blood glucose was significantly higher in men. The prevalence of type 2 diabetes, plasma glucose of 126 mg/dl or greater, and/or antidiabetic medication was also higher for men. However, this prevalence was equal to or lower than that found in other Japanese epidemiological studies of community-dwelling persons (32, 33, 34). Only 43% of subjects who were diagnosed as type 2 diabetes mellitus were receiving antidiabetic medications. This ratio is similar to that reported by the Funagata diabetes study for rural Japanese (47% of treatment ratio) (35) and the national survey for the prevalence and clinical background of diabetic subjects by the Japanese Ministry of Health, Labor, and Welfare (50.6%).

Factors associated with plasma HMW adiponectin levels

Associations between various clinical characteristics and plasma HMW adiponectin levels are summarized in Table 2Go. HMW adiponectin levels were positively associated with age for both men and women. Plasma HDL-cholesterol levels were also positively associated with adiponectin levels. In contrast, an inverse association was observed with BMI and hsCRP. After adjusting for other confounding factors, these associations were still significant (Table 2Go).

In the male subjects, regular smoking and alcohol intake were associated with reduced HMW adiponectin levels (Table 3Go). In the female subjects, alcohol intake was also related to reduced HMW adiponectin levels; however, we found no distinct association with smoking, probably because of the small number of female subjects who were regular smokers.


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  		TABLE 3. Plasma HMW adiponectin levels (micrograms per milliliter), compared with various characteristics of the subjects

 
Plasma HMW adiponectin level and MetS

Table 3Go represents the relationships between five metabolic disorders and plasma HMW adiponectin levels. All subjects, both men and women, with metabolic disorders (except for raised BP) had significantly lower plasma adiponectin levels. Subjects with raised BP were on average older than normotensive subjects (male, 64 ± 12 vs. 52 ± 15 yr, P < 0.001; female, 67 ± 9 vs. 55 ± 13 yr, P < 0.001). Because plasma HMW adiponectin levels significantly increased with age (Table 2Go), advanced age may account for the inverse association between raised BP and increased HMW adiponectin levels.

The accumulation of metabolic disorders was inversely associated with the HMW adiponectin concentrations (Fig. 1Go, A and C). Because subjects with raised BP had higher HMW adiponectin levels due to advanced age, we carried out subanalyses on subjects younger than 65 yr. The accumulation of metabolic disorders was also related to the adiponectin levels in these subjects (Fig. 1Go, B and D). Table 3Go represents plasma HMW adiponectin levels in subjects with or without MetS by gender and age. In addition to gender differences, advanced age could also be a potent modifiable factor for the relationship between MetS and plasma HMW adiponectin. Plasma HMW adiponectin was also inversely associated with HOMA-IR (male, r = –0.315, P < 0,001; female, r = –0.331, P < 0.001).

Plasma hsCRP levels and MetS

Subjects with MetS showed significantly higher plasma hsCRP levels (0.11 ± 0.11, 0.07 ± 0.08, P < 0.001). This was also the case for a separate analysis by sex (male, 0.12 ± 0.11, 0.08 ± 0.09, P < 0.001; female, 0.11 ± 0.10, 0.06 ± 0.07, P < 0.001). All five metabolic disorders showed positive associations with hsCRP levels (P < 0.001). Plasma hsCRP levels were also positively associated with HOMA-IR (male, r = 0.221, P < 0.001; female, r = 0.303, P < 0.001).

Logistic regression analysis for MetS

We carried out a logistic regression analysis to further clarify the associations among HMW adiponectin, hsCRP, and MetS (Table 4Go). Reduced plasma adiponectin and elevated hsCRP levels were potent and independent determinants of MetS. These two molecules were also independently associated with insulin resistance, defined as HOMA-IR greater than 1.73. Because several studies used a higher value of HOMA-IR as the cutoff point of insulin resistance, we carried out further analysis using HOMA-IR greater than 2.5 as a cutoff value (36). After adjusting for other confounding factors listed in Table 4Go, HMW adiponectin (odds ratio 0.079, P < 0.001) and hsCRP (odds ratio 2.809, P < 0.001) were found to be independent determinants for insulin resistance.

Synergistic effects of HMW adiponectin and hsCRP

In addition to their direct associations, we observed a synergistic effect between HMW adiponectin and hsCRP (Fig. 2Go). In Fig. 2Go, subjects are divided into tertiles according to HMW adiponectin and hsCRP levels within gender and then combined to avoid the gender differences in HMW adiponectin concentrations. We assessed the statistical significance of the synergistic relationship using a general linear model with the following confounding factors: age, sex, current smoking, alcohol intake, and history of CVD. The interaction between reduced HMW adiponectin and elevated hsCRP was a significant and independent determinant for the accumulation of metabolic disorders (F = 11.8, P = 0.001), in addition to their direct associations (HMW adiponectin, F = 58.6, P < 0.001; hsCRP, F = 47.0, P < 0.001). The synergistic association was also observed for log normalized HOMA-IR (F = 10.5, P = 0.001; medication was further adjusted).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To the best of our knowledge, this is the first study to indicate an association of HMW adiponectin (but not total adiponectin) with insulin resistance and MetS in more than 1000 community-dwelling subjects. We have also demonstrated the clinical factors associated with the plasma HMW adiponectin levels. Our epidemiological investigation ascertained an experimentally suggested interaction between adiponectin and hsCRP.

It is well known that circulating adiponectin levels are inversely associated with BMI (37). TNF-{alpha} overexpressed in adipose tissue may be involved in the obesity-related reduction of circulating adiponectin levels (37). A unique state in which adiponectin may be differentially regulated in association with adipose tissue maldistribution has been proposed (11, 38). A reduced expression of adiponectin mRNA in visceral fat rather than sc fat is thought to be another underlying mechanism for the inverse association between plasma adiponectin levels and BMI (39). HMW adiponectin has also been reported to inversely associate with BMI in subjects with type 2 diabetes (18). The present study provides further evidence for the relationship between increased BMI and reduced HMW adiponectin levels in community-dwelling middle-aged to elderly subjects.

Plasma HMW adiponectin levels were significantly higher in female subjects, which is consistent with the findings of a previous report (18). As for total adiponectin, gender differences in fat distribution (11) were thought to be a possible reason for the decreased circulating levels in men. The HMW form’s specific inhibition of secretion by testosterone could be another plausible explanation (40).

Age was positively associated with plasma HMW adiponectin levels. Recently Isobe et al. (41) reported the age-associated elevation of plasma total adiponectin levels in elderly subjects with higher blood urea nitrogen levels. Aso et al. (18) reported an inverse relationship between creatinine clearance and circulating HMW adiponectin levels, as well as total adiponectin levels, in subjects with type 2 diabetes. Elevated adiponectin levels in both serum and urine were also reported in patients with end-stage renal disease (42) and diabetic subjects with overt nephropathy (43). Decreased urinary excretion due to reduced renal function could be a possible explanation for the age-related elevation of plasma adiponectin levels. Because our study investigated only the relationship between HMW adiponectin and MetS in middle-aged to elderly subjects, we cannot exclude the possibility that reduced renal clearance may partially account for our findings. Further investigations will be needed to generalize these findings to the wider population. It would also be useful to evaluate renal function as another considerable factor in the clinical implication of adiponectin.

Reduced HMW adiponectin was significantly related to the development of specific components of MetS: impaired glucose tolerance, hypertriglyceridemia, low HDL cholesterolemia, and obesity. Insulin resistance was thought to be a key factor linking these variables and HMW adiponectin as well as hsCRP. Actually, these two molecules were significantly associated with HOMA-IR. Physiological concentration of adiponectin has been shown to inhibit the expression of adhesion molecules, the TNF-{alpha}-induced nuclear factor-{kappa}B activation, and the expression of the scavenger receptor class A-1 of macrophages, which results in a markedly decreased uptake of oxidized low-density lipoprotein and inhibition of foam cell formation (44). These vascular cellular functions could be underlying physiological mechanisms linking reduced adiponectin and insulin resistance.

In this study we observed an inverse association between HMW adiponectin and hsCRP levels. Aso et al. (18) reported the same relationship in both total and HMW adiponectin. Ouchi et al. (22) reported a reciprocal association between adiponectin and hsCRP mRNA expression levels in human adipose tissue: CRP mRNA levels in adipose tissue were increased in adiponectin knockout mice. On the other hand, adiponectin suppresses the proinflammatory effects of TNF-{alpha} (37). TNF-{alpha} could modulate hepatic CRP synthesis, a main resource of circulating CRP, by altering IL-6 action. Therefore, adiponectin could influence the CRP synthesis by both directly modulating CRP mRNA expression in adipose tissue and indirectly modulating hepatic CRP synthesis. The biphasic effect of adiponectin on CRP synthesis is a plausible explanation for the synergistic interaction between reduced HMW adiponectin and elevated hsCRP.

There are several limitations to this study. First, we did not measure total adiponectin levels. The significant associations observed in this study may not be common in other forms of adiponectin. The effects of each molecular isoform of adiponectin should also be clarified. Second, we did not include waist to hip ratio or a parameter of body fat distribution because this epidemiological survey was carried out before the definition of MetS was published (1). Finally, we defined obesity as a BMI of more than 25 kg/m2 following the guidelines of the Japanese Society of the Study of Obesity (25). We chose this definition because mean BMI is lower in the Japanese than Caucasians. In fact, the percentage of subjects in our study with a BMI 30 kg/m2 or greater (the obesity criterion defined by the World Hearth Organization and the National Institute of Health in the United States) was only 2.6% of men and 2.9% of women.

In conclusion, we have clarified the synergistic association between plasma HMW adiponectin and hsCRP levels for MetS. These findings have important clinical implications for identifying at-risk populations.


   Footnotes
 
This work was supported by a Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology of Japan; a Grant-in-Aid for Scientific Research from The Ministry of Health, Labor, and Welfare of Japan; and a Grant-in-Aid for Scientific Research from the Japan Arteriosclerosis Prevention Fund.

Disclosure Statement: The authors have nothing to disclose.

1 Y.T. and H.O. contributed equally to this work. Back

First Published Online December 26, 2007

Abbreviations: BMI, Body mass index; BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; HMW, high molecular weight; HOMA-IR, homeostasis model assessment of insulin resistance; hs, high-sensitivity; MetS, metabolic syndrome.

Received February 20, 2007.

Accepted December 17, 2007.


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